Oral Edaravone – Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis

ABSTRACT

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.

Areas covered

The authors performed a review of the published literature using the United States (US) National Library of Medicine’s PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.

Expert opinion

Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.

KEYWORDS:

• Amyotrophic lateral sclerosis
• clinical trials
• edaravone
• neuromuscular degeneration
• oral formulation
• safety

1. Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neuromuscular disease characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord, respectively [1]. Patients with ALS typically present with focal limb weakness or bulbar dysfunction progressing to muscle paralysis, dysphagia, respiratory failure, and ultimately death [1]. Following symptom onset, there is a 50% mortality rate within the next 30 months and an average life expectancy of 3 to 5 years [1,2]. A diagnosis of ALS is routinely achieved 10 to 16 months after symptom onset [3], further shortening the potential opportunity for effective treatment. As no cure exists for ALS to satisfactorily and effectively reduce or stop the disease progression, therapeutic clinical strategies focus on symptom management and use of assistive devices to provide palliative care, extend survival, and improve quality of life, including the goal of prolonged patient independence [4].

Only four active pharmaceutical agents have been approved by the United States (US) Food and Drug Administration (FDA) for use in patients with ALS: riluzole, edaravone, sodium phenylbutyrate and taurursodiol (PB-TURSO), and tofersen [5–8]. Edaravone is a free radical scavenger that has demonstrated effects in the reduction of oxidative stress, providing a cytoprotective effect for nerve cells [9]. Free radicals are believed to be associated with the pathology of motor neuron death seen in ALS [10]. However, the mechanism of action (MOA) by which edaravone exerts its therapeutic effect in patients with ALS has not been completely elucidated [6]. Intravenous (IV) edaravone (Radicava®/Radicut®, Mitsubishi Tanabe Pharma Corporation [MTPC]) was initially approved in Japan in 2015, and then was FDA approved in May 2017 with subsequent availability in the US in August 2017 [6]. FDA approval of IV edaravone was based on MTPC Study 19 (MCI186–19), which was a phase 3, randomized, placebo-controlled, double-blind, pivotal clinical trial in patients with ALS [11]. This review focuses on oral edaravone (Radicava ORS®, MTPC), which was approved by the US FDA in May 2022 and available to US healthcare providers in June 2022 [6]. This approval was based on the pivotal clinical trial for IV edaravone [11], and the submission of both the 24-week results of a global phase 3 study evaluating the safety and tolerability of oral edaravone (Study A01; MT-1186-A01) [12] and the clinical pharmacology study comparing the pharmacokinetics of IV and oral edaravone (Study J03; MT-1186-J03) [13].

2. Overview of the market

Each year, approximately 2–3 per 100,000 persons are diagnosed with ALS globally [14], with increasing age [15], male sex [16], White race [17], and military personnel [18] noted as amongst the strongest risk factors for the development of ALS. Since ALS was first described over 150 years ago, numerous studies have attempted to understand the multiple pathological mechanisms contributing to its clinical heterogeneity [19]. This complex pathology of ALS may further explain why most attempts at clinical drug development have resulted in failure, and why existing FDA-approved active pharmaceutical agents for ALS are unable to halt or reverse the disease progression [20].

2.1. What are the unmet needs of currently available therapies?

Riluzole, a neuroprotective anti-glutamatergic oral drug that was FDA approved in 1995, was the first option available to patients in the US for the treatment of ALS [5]. At that time, riluzole was the only approved drug on the market that had been shown to extend survival in patients with ALS, and the original analyses of data from randomized controlled trials (RCTs) suggested that it typically does so by 2–3 months [5,21–23].

In September 2022, the FDA also approved Relyvrio™ (Amylyx Pharmaceuticals; approved as Albrioza™ in Canada), which is an oral, fixed-dose combination therapy containing PB-TURSO [7]. PB-TURSO significantly slowed the loss of physical function in patients with ALS in the 24-week phase 2 CENTAUR clinical trial [24] and resulted in longer median overall survival vs placebo in a follow-up open-label extension (OLE) [25].

Finally, in April 2023, the FDA approved QALSODY™ (tofersen) injection for intrathecal use in patients with ALS who have a mutation in the superoxide dismutase 1 (SOD1) gene [8]. Tofersen is an antisense oligonucleotide and is the first FDA-approved treatment to target a genetic cause of ALS. It was granted an accelerated approval based on reduction in plasma neurofilament light chain (NfL), which is a marker of neurodegeneration, that was observed in tofersen vs placebo group patients with ALS. Tofersen was associated with reductions in plasma NfL and SOD1 protein in the cerebrospinal fluid. Continued approval may be contingent upon confirmation of clinical benefit in the ongoing phase 3 ATLAS study in patients with presymptomatic SOD1-ALS [26].

Of these FDA-approved active pharmaceutical agents, each one theoretically targets a different ALS pathway. While no clinical data exists regarding the efficacy of combination therapy, their unique mechanisms of action offer hope that combination therapy may ultimately lead to functional and survival benefits. The safety of combination therapy for patients with ALS has been demonstrated in previous clinical trials. First, greater than 90% of patients in Study 19 were also taking riluzole [11]. Additionally in the CENTAUR trial, 71% of patients were receiving riluzole, 34% of patients were receiving IV edaravone, and 28% of patients were receiving both riluzole and IV edaravone [24]. We now review oral edaravone as a treatment option with a favorable safety profile for patients with ALS and provide information on IV edaravone as it relates to the development of the oral formulation.

3. Introduction to the drug

The specific MOA of edaravone in patients with ALS remains unknown [6]. Although many disease altering genes have been implicated in ALS pathogenesis, edaravone has been reported to work through several possible mechanisms, which include preventing oxidative stress-induced motor neuron death and preventing proteinopathy by reducing misfolding of ALS-associated proteins [27–30].

3.1. Edaravone chemistry and ingredients

Edaravone is a member of the substituted 2-pyrazolin-5-one class, with a chemical name of 3-methyl-1-phenyl-2-pyrazolin-5-one, molecular formula C₁₀H₁₀N₂O [6]. Oral edaravone is a white to off-white, opaque, homogenous suspension containing 105 mg of edaravone per 5 mL of suspension, with the following inactive ingredients: L-cysteine hydrochloride hydrate, polyvinyl alcohol, simethicone emulsion, sodium bisulfite, sorbitol, and xanthan gum. Patients with hereditary problems of fructose intolerance (eg, fructose, sucrose, invert sugar, and sorbitol) should avoid using oral edaravone. Sodium bisulfite may cause a sulfite allergic reaction in some patients. The addition of xanthan gum is pharmaceutically favorable because it can maintain high dispersibility via increased viscosity of the oral formulation and it may also prevent accidental aspiration during swallowing, which may be favorable for some patients with ALS [31]. Additionally, phosphoric acid and sodium hydroxide are added to adjust to pH 4 [6].

3.2. Pharmacokinetics and bioequivalence studies

Although IV edaravone can be administered in the clinic or at home, IV administration can impose an additional burden on patients and caregivers [32]. Oral edaravone may reduce this burden, and pharmacokinetic (PK) and bioequivalence studies have demonstrated that a 105-mg dose of oral edaravone, administered under fasted conditions, has a similar PK profile to the approved 60-mg dose of IV edaravone [13,31]. In addition, oral edaravone demonstrated similar PK following administration via feeding tubes and oral administration [6,33]. The PK of edaravone was not affected by age in the geriatric population or by gender during clinical trials, and no significant differences in maximum drug concentration (C_max) or area under the curve (AUC) were observed between Japanese and Caucasian subjects [6]. Additionally, published population PK modeling analyses showed no clinically relevant differences in the PK profiles of edaravone by race, sex, weight, or age when comparing Japanese and Caucasian populations [34].

3.3. Administration

Oral and IV edaravone have an identical dosing regimen and are administered in 4-week treatment cycles [6]. The initial treatment cycle consists of daily dosing for 14 days followed by a 14-day drug-free period. Subsequent cycles consist of daily dosing for 10 of 14 days, followed by a 14-day drug-free period. After overnight fasting, oral edaravone should be administered in the morning on an empty stomach, and no food or drink (except water) should be consumed for 1 hour. Patients should be instructed to fast 8 hours before each dose if they consume a high-fat meal (800–1000 calories, 50% fat), 4 hours before each dose if they consume a low-fat meal (400–500 calories, 25% fat), or 2 hours before each dose if they consume a caloric supplement (250 calories, eg, protein drink). Following the administration of oral edaravone to healthy subjects 1 hour before or 8 hours after high-fat meals, 4 hours after low-fat meals, or 2 hours after caloric supplement, the C_max and AUC did not decrease significantly (less than 20% and 10% changes in C_max and AUC, respectively). The effects of the type and timing of meals on C_max and AUC following administration of oral edaravone in healthy subjects are described in Table 1.

Table 1. Effect of the type and timing of meals on the pharmacokinetics of oral edaravone relative to fasted conditions in healthy subjects.

Type and timing of meal consumed	Effect on Cmax and AUC relative to fasted conditions
ORS administered with a high-fat meal	Cmax decreased by 82%, AUC decreased by 61%
ORS administered 4 hours after a high-fat meal	Cmax decreased by 44%, AUC decreased by 24%
ORS administered 2 hours after a low-fat meal	Cmax decreased by 45%, AUC decreased by 21%

AUC, area under the curve; C_max, maximum drug concentration; ORS, oral edaravone.

3.4. Options provided by an oral formulation

In the opinion of the authors, oral edaravone offers flexible administration options, as it is a 5-mL dose that can be administered within minutes either orally or via a PEG/feeding tube using an oral syringe [6]. It may be stored at room temperature and therefore is portable enough to be given whether the patient is at home or away. For patients with ALS, the accessibility of oral therapy and ability to manage and sustain this treatment may be preferred when compared to intravenous delivery. This may translate into improved patient and caregiver quality of life by allowing patients more time to focus on their personal life and family, while avoiding nursing interventions associated with infusions. Oral therapy should also decrease caregiver time and transportation responsibilities. Furthermore, oral treatment may reduce healthcare disparities for patients who are geographically unable to access an infusion center or home healthcare service provider. Importantly, based on previous clinical trials where edaravone was used in combination with riluzole, PB-TURSO, and/or tofersen, there is indirect initial evidence supporting the probable safety of combination therapy [8,11,24,26].

4. Clinical efficacy

A series of clinical trials led to the FDA approval of IV edaravone, resulting in the first new drug in over 20 years for patients with ALS since the FDA approval of riluzole. Since then, IV edaravone has been added to the therapeutic regimen of many patients with ALS.

Published real-world, observational studies investigating patients with ALS treated with edaravone have used various methods and reported mixed results [35–37]. Vu et al examined IV edaravone–treated patients with ALS in the US Veterans Affairs (VA) health care system [36]. Use of IV edaravone was associated with lower death rates per 100 patient-years (18.0 for IV edaravone vs 29.3 for riluzole only [hazard ratio (HR), 0.77; 95% CI, 0.43 − 1.18]). These HRs were a comparison of the edaravone vs riluzole-only subgroups and utilized Bonferroni-corrected CIs, but was not found to be statistically significant. While this study used propensity score-matching, the two groups may have still been impacted by residual confounding or baseline differences, possibly due to differences in ALS progression. Additionally, some patients in the control group who were receiving riluzole only had an extended treatment duration due to differential censoring. In a different single-arm, observational study by Lunetta and colleagues, IV edaravone-treated patients in ALS centers in Italy were matched to historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. Notably, concurrent controls were not included. No difference was found in time to clinical outcomes including the time to an ALS Functional Rating Score-Revised (ALSFRS-R) decline to 24 points or time until 60% forced vital capacity (FVC) was reached [35]. Time-to-events were measured using a multivariable Cox proportional hazards regression model, adjusted for by age, site of onset, diagnostic delay, and disease progression rate. Finally, another single-arm, observational study from the German Motor Neuron Disease Network (MND-NET) did not report increased survival during a median follow-up of 11.4 months (interquartile range 6.6 − 18.9 months) [37]. Contemporaneous controls were not included; instead non–IV edaravone-treated patients from the MND-NET were assigned as controls. Finally, propensity score matching for the treated and control groups compared only four covariates including site of disease onset, age at onset, disease duration, and baseline ALSFRS-R score.

As drug formulation, dosing regimens, and route of administration can impact patients’ quality of life and disease outcomes [38], the development of an oral formulation was pursued. We now review the pivotal phase 3 trial for IV edaravone, Study 19, the clinical trials preceding it, and the subsequent oral edaravone clinical trial development program.

4.1. Study 19 (MCI186–19) and post hoc analyses

Study 19 (MCI186–19) was a randomized, double-blind, parallel-group, placebo-controlled, pivotal phase 3 trial designed to establish the safety and efficacy of IV edaravone for the treatment of ALS [11]. The details of the 24-week double-blind period and 24-week open-label active treatment period have been previously described (clinicaltrials.org: NCT01492686) [11,39]. Prior to Study 19, treatment with IV edaravone in an earlier phase 3 Study 16 (MCI186–16) suggested a benefit but did not show a significant difference between study arms. This was believed to be due to the clinical heterogeneity seen in patients with ALS. Specifically, post hoc analyses of placebo patients in Study 16 showed that compared with the Full Analysis Set, subsets of these patients with greater baseline functionality, more definitive diagnoses, and more rapid progression exhibited a significant decline in their ALSFRS-R score at the end of 24 weeks, providing a better chance of identifying a treatment effect [40,41]. Study 19 utilized a clinical trial enrichment strategy from the Study 16 post hoc analyses to determine a treatment effect over 6 months, based on the ALSFRS-R score [2,42–44]. This enrichment strategy enrolled patients who had met certain functional parameters at baseline, including an ALSFRS-R score of 4 on the respiratory items and a FVC ≥ 80% [2,11,44]. Additionally, there was a lead-in period during which patients were excluded from randomization if they did not show evidence of ALS progression, as indicated by a 1-2–point ALSFRS-R score decline.

The primary efficacy analysis included an IV edaravone (n = 68) and placebo (n = 66) group [11]. Over 24 weeks, the ALSFRS-R score change was −5.01 (standard error [SE] 0.64) in the IV edaravone group and −7.50 (0.66) in the placebo group. The least-squares mean difference between groups was 2.49 (SE 0.76, 95% CI 0.99 − 3.98; P = 0.0013) in favor of IV edaravone. Treatment-emergent adverse events (TEAEs) were reported in 58 (84%) patients in the IV edaravone group and 57 (84%) patients in the placebo group.

Although Study 19 used an enrichment strategy to select for the enrolled population, previous publications have shown that the results of Study 19 may be generalized to a broader cohort of patients with ALS beyond only those included in the trial [45–48]. First, a Study 16 post hoc analysis used a machine learning method to demonstrate that up to 70% of Study 16 patients would have received statistically significant benefits [47]. Further, there was a post hoc analysis of the 24-week OLE which followed the Study 19 double-blind period [48]. At the start of the OLE when all patients were administered IV edaravone, 15% of patients in the placebo-edaravone group (placebo for 24 weeks, then IV edaravone) met the Study 19 inclusion and exclusion criteria. Despite this, the ALSFRS-R score decline for placebo-edaravone patients at week 48 was lower than the estimated decline projected, had patients remained on placebo for 48 weeks (−10.9 vs − 13.0, respectively). Another Study 19 post hoc analysis reported a 33% decreased loss in ALSFRS-R score for patients who received edaravone for 48 weeks (edaravone-edaravone group) vs placebo-edaravone patients (−10.26 vs −15.20, respectively; P = 0.0038) [46]. In a previously reported survey, 100% of participating ALS experts indicated that a 25% decrease in ALSFRS-R slope was at least somewhat clinically meaningful [49]. Furthermore, an observational administrative claims analysis of propensity score matched (PSM) IV edaravone–treated vs IV edaravone–naïve patients with ALS in the US evaluated survival. This study found a 27% lower risk of death in the IV edaravone–treated vs IV edaravone–naïve group (HR, 0.73; 95% CI, 0.59 – 0.91; P = 0.005), indicating that IV edaravone treatment was correlated with a survival benefit relative to no prior IV edaravone treatment. There were some limitations of this study. First, only patients with ALS who had commercial or Medicare Advantage insurance plans were included. Consequently, patients with ALS who are uninsured or insured under other health plans may not have the same results. Also, inherent limitations exist due to the administrative claims data source, such as the possibility for ALS underdiagnosis, which could create a bias in the selected study population. While PSM controlled for variability between the IV edaravone–treated and IV edaravone–naïve groups, matching was limited to available administrative claims data. As a result, patients in the study groups may have appeared healthier than the total population of patients with ALS [45].

4.2. Oral edaravone clinical trial development program

Patients have reported that they prefer medication administered orally over other routes of delivery [50–52]. Some reasons patients do not prefer injections or infusions include the increased frequency of office visits for medication administration and monitoring for potential injection-site reactions or other injection-/infusion-specific side effects. The oral edaravone clinical trial development program was initiated, in part, to address these preferences. Preclinical toxicology studies in animals reported consistent results for IV and oral edaravone [6]. Subsequently, seven phase 1 clinical pharmacology studies were conducted (Table 2). Phase 1 studies in healthy subjects did not indicate any effects of race on oral edaravone pharmacokinetics and no notable drug-drug interaction effects possibly caused by oral edaravone [31].

Table 2. Oral edaravone (MT-1186) clinical trials.

	Oral edaravone clinical trial (ClinicalTrials.gov identifier)	Description
Phase 1	MT-1186-J01 (NCT04481750)	Placebo-controlled, randomized, dose-ranging evaluation of the PK, safety, and tolerability of oral edaravone in healthy adult males studying single and multiple ascending doses of oral edaravone Evaluated the Cmax and AUC values of the 105 mg of oral edaravone dose vs the 60-mg/60-minute IV edaravone dose
	MT-1186-J02 (NCT04481789)	Co-administration of oral edaravone with other drugs to determine drug-drug interactions in healthy adult males Preliminary regimen-finding study investigating food and the effect of Japanese vs Caucasian race on the PK of oral edaravone in healthy adult males
	MT-1186-J03 (NCT04493281)	Single-dose, randomized, 2-period, 2-sequence crossover, open-label study that evaluated the bioequivalence between the 60-mg IV edaravone dose and the 105-mg oral edaravone dose in healthy adult subjects
	MT-1186-J04 (NCT04176224)	Single-dose, open-label clinical pharmacology study that investigated the PK and safety of oral edaravone in adult Japanese patients with ALS vs healthy volunteers
	MT-1186-J05 (NCT04254913)	Single-dose, open-label study that investigated the difference in PK and safety of the administration of oral edaravone in patients with ALS via a PEG tube vs historic oral administration
	MT-1186-J06 (NCT05342597)	Single-dose, randomized, open-label, crossover study evaluating food effect on the PK of 105 mg of oral edaravone in healthy adult Japanese participants
	MT-1186-Z-101 (NCT04776135)	Randomized, open-label, crossover, single-dose clinical pharmacology study investigating the safety, tolerability, and comparative bioavailability of oral edaravone administered orally and via a nasogastric tube (as a surrogate for PEG/RIG administration) in healthy adult volunteers
Phase 3	MT-1186-A01 (NCT04165824)	Open-label, multicenter safety study evaluating the safety and tolerability of oral edaravone in patients with ALS using the FDA-approved dosing schedule over a 48-week treatment period
	MT-1186-A03 (NCT04577404)	Long-term safety and tolerability extension study for patients with ALS who complete Study A01 and will continue to receive oral edaravone without interruption for an additional treatment period of 96 weeks
	Extension of MT-1186-A03 (NCT05568615)	Ongoing, multicenter, single-group, open-label extension study following Study A03 to evaluate the safety of the FDA-approved on/off dosing regimen of oral edaravone in Japanese adults with ALS

Note: ALS, amyotrophic lateral sclerosis; AUC, area under the curve; C_max, maximum drug concentration; FDA, Food and Drug Administration; IV, intravenous; PEG, percutaneous endoscopic gastrostomy; PK, pharmacokinetics; RIG, radiologically inserted gastrostomy; TEAE, treatment-emergent adverse event.

Study MT-1186-A01 (A01) was a global, multicenter, open-label, phase 3 study that evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a diagnosis of definite, probable, probable laboratory-supported, or possible ALS, according to El Escorial revised Airlie House diagnostic criteria; baseline FVC ≥ 70% of predicted; disease duration ≤ 3 years; and ability to function independently [12]. Additional information about Study A01 has been previously published, including primary safety analyses at 24 and 48 weeks, and is briefly described here. Study A01 included a screening period of up to 3 weeks, followed by an open-label treatment period, where patients received a 105-mg dose of oral edaravone in treatment cycles that replicated the IV edaravone dosing. FDA approval of oral edaravone was based, in part, on the safety analyses at 24 weeks. The Safety Analysis Population included 185 patients, with 139 patients completing 48 weeks of therapy. During the 48-week study period, 94.6% of patients reported a TEAE and 25.9% of patients reported a serious TEAE, all of which were generally consistent with the disease state. No serious TEAEs related to the study drug were reported. A total of 13 TEAEs leading to death in 12 patients were reported, of which none were considered by the investigator to be related to the study drug. FVC gradually declined during the study period, and FVC results were consistent with previous clinical trials with IV edaravone. Study A01 indicated that oral edaravone was well tolerated over 48 weeks and the safety results were generally consistent with the IV edaravone safety profile, with no new safety concerns identified. The safety data from this trial, combined with existing evidence for IV edaravone, support the use of FDA-approved oral edaravone. After the completion of Study A01, all patients were given the option to transfer to Study A03 (MT-1186-A03; NCT04577404), which is an open-label, ongoing, 96-week safety extension study of oral edaravone in patients with ALS [53].

5. Post-marketing surveillance

Since oral edaravone has been available to patients for less than 1 year, most of the safety data are currently from studies of IV edaravone. Real-world post-marketing pharmacovigilance data were published containing data from the first 3 years after IV edaravone became available to patients with ALS in the US, with a focus on infusion-related safety data [54]. SUNRISE Japan is an ongoing post-marketing observational surveillance study that is assessing the real-world safety and efficacy of IV edaravone in patients with ALS over a 5-year period [55]. This included the incidence of adverse drug reactions (ADRs) up to 1 year after treatment initiation among 800 Japanese patients with ALS treated with IV edaravone [56]. Abnormal hepatic function was the most frequently reported ADR (4.4%), which was commonly reported for patients receiving concomitant riluzole and may be associated with its known hepatic impact. Several phase 3 studies for oral edaravone are currently underway (Table 2).

6. Regulatory affairs

IV edaravone was approved for the treatment of ALS in Japan and South Korea in 2015, and by the US FDA in 2017. Marketing authorizations were subsequently granted in Canada (2018), Switzerland (2019), China (2019), Indonesia (2020), and Thailand (2021) [57,58]. Oral edaravone was approved by the US FDA in May 2022, by Canada in November 2022, by Japan in December 2022, and by Switzerland in May 2023.

7. Conclusion

ALS is a progressive and incurable neurodegenerative disease, and pharmacotherapy options remain limited since ALS was first described approximately 150 years ago. Edaravone was the first drug shown to slow the rate of motor function deterioration experienced by patients with ALS. The US FDA-approved options of IV or oral edaravone, in addition to riluzole, PB-TURSO, and tofersen (for patients with a mutation in the SOD1 gene), are now available to patients with ALS to help delay their functional decline. With the addition of oral edaravone, patients with ALS may exclusively use oral medications. Ongoing studies and real-world evidence will provide additional understanding of the clinical profiles and combination use of these drugs in patients with ALS.

8. Expert opinion

Historically, the development of effective drug therapies for ALS has been a major challenge. ALS displays clinical heterogeneity in its presentation and exhibits multiple pathogenic mechanisms [19], including genetic factors, and future trials should take this into consideration with the use of enrichment designs. Despite this heterogeneity, common pathologic alterations in ALS such as neuroinflammation, aberrant protein aggregation, and excessive oxidative stress have been confirmed [19,59]. Within this context, the development of therapeutic strategies capable of interfering with each of these putative pathologic alterations, and incorporating a ‘cocktail approach’ of interventional treatment, may result in an effective strategy. Although the mechanism of action of edaravone has yet to be clearly elucidated [6], as a free radical scavenger it represents a therapeutic option which, in combination with other treatments, could counteract the proposed pathogenic mechanism of oxidative stress inducing motor neuron damage in ALS [9]. As oxidative stress is a known trigger of inflammation leading to neuronal cell loss, an effective antioxidant therapy for ALS may counteract neuroinflammation and preserve neurons. This prevention of motor neuron deterioration is essential, as degenerative motor neurons cannot be rescued. Understanding that an early clinical diagnosis is vital, the emergent need for validated biomarkers in ALS is critical. Biomarkers may serve to shorten time to diagnosis, provide information on therapeutic efficacy, and track disease progression. They will also provide insights into the pharmacodynamics and bioavailability of drugs in clinical studies. In recent years, this field has exploded with the advent of technological platforms, including genetic and proteomic strategies poised to make such discoveries possible. Congruent with this, the REFINE-ALS study (NCT04259255) may help clarify the mechanism of edaravone on ALS pathogenesis through the prospective longitudinal analysis of various biomarkers in ALS patients treated with edaravone [60].

The clinical experience of the authors would conclude that oral edaravone represents an important treatment option that may provide easier patient access to disease modifying therapy, yet also may allow for continuation of treatment regardless of patient functional status or available health services. The US availability of four currently approved active pharmaceutical agents (riluzole [5], edaravone [6], PB-TURSO [7], and tofersen [8]) and the propensity of patients with ALS willing to take any available drug that might slow disease progression, will allow for real-world identification of the safety of these drug combinations, including changes in the natural history of ALS. Projects such as the ALS Natural History Consortium which creates datasets to describe this history will be helpful in identifying information regarding the impact and effect of drug combinations on patients with ALS [61].

9. Five-year view

Over the next 5 years, the ALS field will see the development of increasingly precise biological characterization strategies aimed at identifying the best therapeutic approach for each patient. For example, the ongoing phase 3 ATLAS study of the FDA-approved antisense oligonucleotide against SOD1 is the first interventional trial in presymptomatic carriers of a SOD1 mutation and is designed to evaluate whether treatment can delay the clinical onset of ALS [26]. Additionally, in the next 5 years, there will be development of new therapeutic strategies aimed at counteracting common pathogenic mechanisms, including oxidative stress, protein aggregation, neuroinflammation, and others [62]. New treatment options have the potential to complement already approved drugs, which may enable a therapeutic synergy against these and other pathogenic mechanisms. Identification of biomarkers will also make it possible to detect patients in the initial stages of ALS, when therapies may be most able to diminish or halt disease progression. Furthermore, longitudinal characterization of various biomarkers within the earliest stages of ALS will further clarify overall disease progression and the impact of available treatment options, optimizing appropriate timing for the initiation of these therapeutic strategies.

Article highlights

• While the exact mechanism of action remains unknown, edaravone acts as a free radical scavenger that has demonstrated reduction of oxidative stress, which is believed to be associated with the pathology of ALS

• Edaravone is a US FDA-approved drug shown in clinical trials to slow the rate of physical functional decline in patients with ALS, and is one of only four FDA-approved active pharmaceutical agents for ALS

• Study 19 (MCI186-19) was a randomized, double-blind, parallel-group, placebo-controlled phase 3 trial designed to establish the safety and efficacy of IV edaravone for the treatment of ALS

• Oral edaravone was FDA approved in May 2022 based on the 24-week results of a global phase 3 study evaluating its safety and tolerability (Study A01; MT-1186-A01) and a clinical pharmacology study that compared the pharmacokinetics of IV and oral edaravone (Study J03; MT-1186-J03)

• Oral edaravone can be administered orally or through a nasogastric/percutaneous endoscopic gastrostomy tube

• Additional clinical studies and real-world evidence will be helpful in gaining an improved understanding of the benefits of oral edaravone alone and in combination with other approved ALS therapeutics

Declaration of interest

GL Pattee and A Genge have served as consultants for Mitsubishi Tanabe Pharma, Inc. P Couratier has served as a consultant for Biogen and as an editor for Elsevier. C Lunetta has served as a scientific consultant for Mitsubishi Tanabe Pharma Europe, Cytokinetics, Neuraltus, and Italfarmaco. G Sobue, M Aoki and H Yoshino have served as medical advisors for Mitsubishi Tanabe Pharma Corporation. C Jackson serves on the Data and Safety Monitoring Board for Mitsubishi Tanabe Pharma America, Inc., and Anelixis. J Wymer has received research funding from Mitsubishi Tanabe Pharma America, Inc. A Salah is an employee of Mitsubishi Tanabe Pharma America, Inc., and S Nelson is a former employee of Mitsubishi Tanabe Pharma America, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Irene Brody, VMD, PhD, of p-value communications, Cedar Knolls, NJ, USA, for providing medical writing support, which was funded by Mitsubishi Tanabe Pharma America, Inc., Jersey City, NJ, USA, in accordance with Good Publication Practice Guidelines 2022.

Additional information

Funding

This article was funded by Mitsubishi Tanabe Pharma America, Inc.